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Signal."],"published-print":{"date-parts":[[2026,7,21]]},"abstract":"<jats:p>\n                    Cancer cells exploit DNA repair to overcome damage and errors induced by rapid proliferation and repressed checkpoints. Thus, the loss of one DNA repair protein can make tumors more susceptible to inhibition of other repair pathways. Here, using in silico methodologies and high-content genetic and cell survival screens, we found that the antimalarial drug quinacrine impaired the DNA damage response (DDR) in multiple cancer cell lines. Quinacrine disrupted the interaction of the stress-response protein NDRG1 with the major segregase VCP, which in turn promoted the degradation of the E3 ubiquitin ligase RNF8 and other proteins that mediate the recruitment of the critical DDR protein 53BP1 to sites of DNA damage. This impaired recruitment of 53BP1 caused increases in the DNA damage marker \u03b3H2AX. High\n                    <jats:italic toggle=\"yes\">NDRG1<\/jats:italic>\n                    expression in tumors correlated with poor survival in patients, and high expression in various cancer cell lines correlated with quinacrine sensitivity. Colorectal carcinoma cells were particularly vulnerable to pharmacological or genetic inhibition of NDRG1, and high\n                    <jats:italic toggle=\"yes\">NDRG1<\/jats:italic>\n                    expression and mutations in\n                    <jats:italic toggle=\"yes\">MLH1<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">PARP3<\/jats:italic>\n                    resulted in synthetic lethality. Our findings identify combination genetic markers that might be therapeutically exploited in colon cancer, as well as provide a platform for such discovery in distinct cancer types.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.adv4272","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T17:58:44Z","timestamp":1784656724000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["<i>NDRG1<\/i>\n                    expression in cancers confers dependence on DNA damage repair and sensitivity to quinacrine"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5704-7219","authenticated-orcid":true,"given":"Garik V.","family":"Mkrtchyan","sequence":"first","affiliation":[{"name":"Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, 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